An investigation will be made of the inactivation of human plasma protease inhibitors (PPI) by snale venom proteases. Preliminary experiments by the principal investigator indicate that protease(s) from Crotalus adamanteus venom enzymatically inactivate human alpha 1 protease inhibitor (alpha 1 PI) by limited proteolysis of the inhibitor molecule. Related experiments show that the inhibitors alpha 2 macroglobulin (alpha 2 M), alpha 1 chymotrypsin inhibitor (alpha 1 X), inter alpha trypsin inhibitor (I alpha I) and antithrombin III (AT III) are also inactivated by venom protease(s). The research will initially involve purification and characterization of the vneom protease(s) and a study of the mechanism of inactivation of alpha 1 PI. The composition of the inactivation products will be determined, and an attempt made to locate the region of the inactivating cleavage in the inhibitor molecule. Purification of venom proteases inactivating alpha 2 M, AT III, I alpha I, and alpha 1 X will then be carried out. The mechanism of inactivation of these plasma protease inhibitors will be studied and compared to that determined for alpha 1 PI. The objective of the proposed investigation is to further knowledge of the mechanism of interaction between PPI and proteolytic enzymes. A better understanding of the role of proteolysis in the homeostatic imbalances following snake bite should result. The inactivating proteases could prove useful in studying the role of PPI in the biological control of physiological processes. The proteases may also be applicable to animal model systems for in vivo studies of human diseases (e.g., emphysema) which are known to involve deficiencies of specific PPI.